1. Field of the Invention
This invention relates to a method of treating congestive heart failure by increasing cardiac performance without increasing myocardial oxygen consumption. In particular, the invention relates to a method of treating congestive heart failure with compounds that partially inhibit fatty acid oxidation. This invention also relates to pharmaceutical formulations that maintain plasma concentrations of such compounds at therapeutically effective levels for extended periods of time.
2. Background
Congestive heart failure (CHF) is a major cause of death and disability in industrialized society. It is not a disease in itself, but a condition in which the heart is unable to pump an adequate supply of blood to meet the oxygen requirements of the body""s tissues and organs. As a result, fluid accumulates in the heart and other organs, such as the lungs, and spreads into the surrounding tissues. CHF is often a symptom of cardiovascular problems such as coronary artery disease, myocardial infarction, cardiomyopathy, heart valve abnormalities, and the like.
Conventionally, CHF has been treated with a wide variety of drugs, including alpha-adrenergic agonists, beta-adrenergic antagonists, calcium channel antagonists, cardiac glycosides, diuretics, nitrates, phosphodiesterase inhibitors, prazosin, and a variety of vasodilators. All of these drugs, however, have undesirable side-effects. For example, use of alpha-adrenergic agonists results in edema of the peripheral tissues. xcex2-adrenergic agents are effective initially, but prolonged use leads to the progressive development of desensitization to the drug. Treatment with cardiac glycosides is well known to produce toxic side-effects in the CNS, and also the gastrointestinal and respiratory systems. Cardiac glycosides additionally produce pro-arrhythmic effects. Treatment with diuretics may result in a variety of adverse-effects, the most severe of which include electrolyte abnormalities, such as hyponatremia, hypokalemia, and hyperchloremic metabolic alkalosis.
Other problems with current methods of treatment of CHF are exemplified by drugs such as calcium channel antagonists, such as verapamil, diltiazem and nifedipine. These agents initially also produce improvement in the symptoms of CHF, but prolonged use of the agents render them ineffective. Moreover, calcium channel antagonists have been shown to increase the mortality rates in patients thus treated, because such compounds act to increase oxygen consumption, which further stresses the compromised heart.
CHF is characterized by progressive left contractile dysfunction. Accordingly, a desirable approach to treating CHF would be one that enhances contractile function by increasing the efficiency of energy production in the heart thereby increasing cardiac output and mechanical performance.
In the normal heart, most of the energy for contractile function is generated by two processes; 1) oxidative phosphorylation of fatty acids, and, to a lesser extent; 2) oxidation of lactate and glucose, although the latter process is the more efficient. However, in patients with CHF, there is a concomitant increase in fatty acids, so that the amount of energy obtained from the relatively inefficient metabolism of fatty acids increases during exercise-induced stress, and the relative amount of energy generated by the more efficient oxidation of glucose and lactate is reduced. Consequently, the failing heart is further compromised by inefficient energy generation.
Therefore, there is a need for providing a method of treating CHF with agents that switch substrate use in the heart from fatty acids to glucose/lactates, thus improving left ventricle function, without increasing the myocardial oxygen requirement. It is also preferred that the drugs do not act directly to stimulate cardiac contractility, or produce side-effects such as changes in blood pressure and/or heart rate, since they are associated with increased mortality in patients with CHF.
U.S. Pat. No. 4,567,264, the specification of which is incorporated herein by reference, discloses compounds said to have calcium entry blockade properties. In particular, one of those compounds, (xc2x1)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide (known as ranolazine) is undergoing clinical trials for the treatment of angina. Despite the drawbacks generally associated with calcium channel antagonists for the treatment of CHF, it has surprisingly been discovered that the compounds disclosed therein do not have the disadvantages noted above. It has been found that the compounds of ""264 exert their beneficial effect as a consequence of having partial fatty acid oxidation (pFox) inhibiting properties, and that they are valuable for the treatment of CHF. In particular, the compounds of the invention switch substrate use in the heart from fatty acids to glucose/lactates, thus improving left ventricle function, while not producing adverse side-effects such as changes in blood pressure and/or heart rate, and do not act directly to stimulate cardiac contractility, all of which would be expected from a calcium entry blocker.
A problem with conventional pharmaceutical formulations of compounds of ""264 is that they have low bioavailability, because the high acid solubility of the compounds results in rapid drug absorption and clearance, causing large and undesirable fluctuations in plasma concentration. Also, such compounds have a short duration of action, thus necessitating frequent oral administration for adequate treatment. There is, therefore, a need for a method for administering the compounds of ""264, in particular ranolazine, in a dosage form that provides sustained therapeutically effective plasma concentrations of ranolazine for the treatment of congestive heart failure.
U.S. Pat. No. 5,506,229, which is incorporated herein by reference, discloses the use of ranolazine for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants.
U.S. Pat. No. 5,472.707, the specification of which is incorporated herein by reference, discloses a high-dose oral formulation employing supercooled liquid ranolazine as a fill solution for a hard gelatin capsule or softgel.
WO0013687, the specification of which is incorporated herein by reference, discloses a sustained release formulation of ranolazine for use in the treatment of angina.
In a first aspect, the invention provides a method of treating congestive heart failure in mammals, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound that partially inhibits fatty acid oxidation, preferably without effect upon heart rate or blood pressure. Administration is preferably as a bolus or a continuous infusion, or a combination of a bolus and continuous infusion, or as an orally active sustained release formulation.
In a second aspect, this invention provides a method of treating congestive heart failure in mammals, comprising administering to a mammal in need thereof a partial fatty acid oxidation inhibitor of Formula I: 
wherein:
R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R1 is methyl, R4 is not methyl;
or R2 and R3 together form xe2x80x94OCH2Oxe2x80x94;
R6, R7, R8, R9 and R10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R6 and R7 together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94; or
R7 and R8 together form xe2x80x94Oxe2x80x94CH2Oxe2x80x94;
R11 and R12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
and the pharmaceutically acceptable salts and esters thereof.
A preferred compound is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide, as a racemic mixture, or an isomer thereof.
In a third aspect, this invention provides a method of treating congestive heart failure in mammals, comprising intravenously administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I, as a bolus or by continuous infusion, or a combination of both.
In a fourth aspect, this invention provides a method of treating congestive heart failure in mammals, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I, as a sustained release pharmaceutical composition, preferably orally.
In a fifth aspect, this invention provides a method of treating congestive heart failure in mammals, comprising administering to a mammal in need thereof a compound of Formula I in a manner that maintains plasma concentrations of the compound at therapeutic levels.
In one preferred embodiment, the compound of Formula I is administered by iv infusion in a manner that provides plasma level of the compound of Formula I of at least (0.35xc2x10.03 ng/ml) 350xc2x130 ng/mL for at least 12 hours.
In a second preferred embodiment, the compound of Formula I is administered as a sustained release formulation that maintains plasma concentrations of the compound of Formula I at a maximum of 4000 ng/ml, preferably between about 850 to about 4000 ng base/mL, for at least 12 hours.